Clinical Manifestations

Sex-linked differences in sporadic behavioral variant frontotemporal dementia (s-bvFTD) are increasingly recognized. Research suggests that females with bvFTD exhibit greater atrophy in affected brain regions than males, despite similar clinical severity. Given that brain atrophy correlates with elevated markers of neurodegeneration, such as neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), we hypothesized that these biomarkers differ between sexes.

Serum NfL and GFAP levels were measured using Simoa in 357 participants (275 with s-bvFTD, 82 with primary psychiatric disorders (PPD)). Biomarker levels were compared between sexes, followed by linear regression analyses stratified by diagnostic group. In a subset of s-bvFTD participants (47 females, 105 males) with available Z-scored cognitive composite scores (including global cognition, executive function, attention and working memory), we performed linear regression using a residuals approach (with age at blood sample (AAS), education, and Z-scored NfL or GFAP as predictor) to assess cognitive reserve.

Females with s-bvFTD had significantly higher NfL and GFAP levels than males (both p <0.05), whereas no sex differences were observed in the PPD group. Within s-bvFTD, higher AAS (β=0.015, 95% CI [0.006-0.023]) and female sex (β=0.223, 95% CI [0.071-0.375]) were associated with higher logNfL. In PPD, higher AAS (β=0.030, 95% CI [0.019-0.042]) correlated with higher logNfL, but no sex effect was observed (β=-0.092, 95% CI [-0.265-0.082]). For GFAP, higher AAS (β=0.030, 95% CI [0.023-0.037]) and female sex (β=0.305, 95% CI [0.183-0.427]) were associated with higher logGFAP in s-bvFTD. In PPD, only AAS (β=0.026, 95% CI [0.012-0.040]) was significant, without a sex effect (β=0.033, 95% CI [-0.177-0.243]). Composite scores were lower in females (female=-0.24 vs. male=0.003), though not significantly (p >0.05). Residuals of linear regression did not differ by sex for both GFAP and NfL (p >0.05). However, NfL (but not GFAP) predicted a steeper cognitive decline in males (β=-0.15, p <0.05) than in females (β=-0.12, p >0.05).

Females with s-bvFTD exhibited significantly higher NfL and GFAP levels. This sex difference is not explained by differences in cognitive reserve. Given that NfL plateaus as disease progresses, these findings suggest that females with s-bvFTD may present at a more advanced disease stage upon clinical presentation.